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Clinical Observations 399

Downloaded from https://onlinelibrary.wiley.com/doi/ by Universität Bern, Wiley Online Library on [22/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

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neal administration of ethanol led to the activation of PSC and fibro- inflammatory responses in the pancreas [33]. Chronic ethanol consumption accelerated pancreatic fibrosis in response to caerulein- induced pancreatitis in rats[34].

Animal studies have suggested that endotoxin in the microbiota might also be involved. Gut permeability is increased in alcoholics, allowing translocation of gram- negative bacteria across the mucosal barrier and allowing bacterial endotoxins to enter the circulation. A combination of Lieber- DeCarli ethanol- enriched diet and repeated injection of lipopolysaccharide (LPS) developed acute acinar cell injury, activation of PSC and fibrosis[35]. Repeated LPS injection caused pancreatic fibrosis in ethanol- fed rats, but not in rats fed the control diet. When ethanol administration was continued, the activation of PSC and fibrosis persisted, but resolved soon after ethanol was discontinued[36]. Conversely, continued alcohol intake perpetuates pancreatic injury by inhibiting apoptosis and promoting the activation of PSC. These findings indicate the importance of abstinence to prevent the progression of acute pancreatitis to CP.

Genetic Factors Predisposing for the Development of ACP

Recent studies have identified several risk loci in ACP. The serine protease inhibitor Kazal type 1 (SPINK1), also known as pancreatic secretory trypsin inhibitor, acts as the first line of defense against prematurely activated intracellular trypsinogen by inhibiting up to 20% of trypsin activity within the pancreas. A meta- analysis of 12 studies showed the association of the SPINK1 c.101A>G (p.N34S) variant with ACP (OR = 5.28, 95% CI:

3.45–8.09) in a Caucasian population, which was smaller than that in idiopathic CP (OR = 13.64, 95% CI: 8.86–

21.00) [37]. The loss- of- function SPINK1 c.194+2T>C (IVS3+2T>C) variant is commonly found in CP patients in east Asia. The SPINK1 c.194+2T>C variant is overrepresented in patients with ACP (OR = 30.59, 95% CI:

16.61–56.34)[38]. The association of the variants in the chymotrypsinogen C gene (CTRC) with ACP has been shown. LaRusch etal.[39] reported that the synonymous CTRC variant c.180C>T (p.G60=) was overrepresented in CP of all etiologies, but not in recurrent acute pancreatitis as compared with controls (16.8% in CP, 11.9% in recurrent acute pancreatitis, 10.8% in controls). The CTRC c.180T allele was overrepresented in ACP patients (20.8%) compared to NACP patients (12.4%) (OR = 1.9, 95% CI: 1.30–2.79). A meta- analysis of four studies showed that the CTRC c.180T allele was overrepresented in CP (OR = 1.99, 95% CI: 1.49–2.67)[40].

A genome- wide or exome- wide approach overcomes the limitations of a candidate gene approach, enabling the discovery of new and unsuspected pancreatitis susceptibility genes. A genome- wide study from North America identified the association of common variants in the CLDN2- MORC4 (rs7057398 and rs12688220) and PRSS1- PR SS2 loci (rs10273639) conferred an increased risk of ACP, but not with alcohol- associated cirrhosis or alcohol dependence [41]. A meta- analysis of five studies from worldwide countries has confirmed the association of PRSS1 rs10273639with ACP (pooled OR = 1.67, 95% CI:

1.56–1.78) [42]. Functional studies indicated that the rs10273639 or rs4726576, which is in perfect linkage disequilibrium with rs10273639, altered the intrapancreatic trypsinogen levels[43]. Importantly, although the degree of association varies, most of the variants associated with ACP have associations with NACP, suggesting common mechanisms for alcohol- related and non- ACP. Another genome- wide study from Europe replicated previously reported risk loci CLDN2- MORC4, CTRC (c.180C>T, p.G60=), PRSS1- PRSS2, and SPINK1 (c.101A>G, p.N34S) in ACP patients [44]. In addition, this study identified CTRB1- CTRB2 (chymotrypsin B1 and B2) as a new risk locus for ACP and NACP. The association within the CTRB1- CTRB2 locus was linked to a 16.6 kb inversion that altered CTRB1/CTRB2 expression, thereby affecting protective trypsinogen degradation. Importantly, the association of the previously reported and new risk loci was observed when compared with chronic alcoholics, suggesting that these loci are associated with the pancreasspecific injury among alcoholics.

Smoking andChronic Pancreatitis

Recent clinical studies have shown that smoking is another important risk factor for CP, and the underlying mechanisms linking smoking and CP are being elucidated. Importantly, ethanol and smoking synergically affect the development and course of CP.

Clinical Observations

There is accumulating clinical evidence that smoking is a dose- dependent risk factor, independent of alcohol, for CP. Smoking is a risk factor for the progression from AP to recurrent AP and CP [45]. Compared to the never smoker or former smoker, current smoker had a risk of recurrent AP (OR = 2.77, 95% CI: 1.69–4.53) and CP (OR = 3.62, 95% CI: 1.98–6.60). There have been several meta- analyses that assessed the risk of CP among smokers. A meta- analysis of 12 studies showed that, compared to lifetime nonsmokers, pooled risk estimates (95% CI)

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400

for current smokers were 2.8 (1.8–4.2) overall and 2.5 (1.3–4.6) [46]. The risk diminished significantly after smoking cessation, as the RR estimate for former smokers dropped to a value of 1.4 (1.1–1.9). A recent systematic review and meta- analysis of 22 studies revealed the summary relative risks (RR) (95% CI) for CP compared to never smokers were 3.00 (1.46–6.17) in ever, 2.72 (1.74–4.24) in current, and 1.27 (1.00–1.62) in former smokers[47]. Another meta- analysis of 10 prospective studies revealed that RR (95% CI) for CP were 1.93 (1.60–2.32) in current smokers, 1.30 (1.08–1.57) in former smokers, and 1.59 (1.39–1.82) in ever smokers compared to never smokers [48]. Dose–response analysis revealed that the summary RR per 10 pack- years was

1.22 (1.11–1.33) for CP. Smoking accelerates the progression of CP. Smoking is

independently associated with earlier onset, recurrence, appearance of calcifications, and diabetes mellitus[49]. Smoking was associated with approximately

year- earlier diagnosis of ACP, and with the appearance

5of pancreatic calcifications (hazard ratio [HR] = 4.9, 95% CI: 2.3–10.5) and diabetes (HR = 2.3, 95% CI: 1.2–4.2), independent of alcohol consumption [50]. The lower risks for CP development and progression in former smoker than those in current smoker suggest that smoking cessation decreases the risk and progression of CP. Smoking cessation would be an important strategy for primary as well as secondary prevention of pancreatitis. In addition to alcohol, physicians should routinely counsel patients for the benefits of smoking cessation. Widespread recognition of the association between smoking and CP could potentially curtail smoking rates in subjects with CP and those at risk of CP[51].

Pathophysiology

Among the more than 4000 compounds in cigarette smoke, effects of cigarette smoke, nicotine, and the tobacco- specific most abundant nitrosamine known as nicotine- derived nitrosamine ketone (NNK) have been studied alone or in combination with ethanol with regard to pancreatic diseases[52]. Major cellular components of the pancreas including pancreatic acinar cells, ductal cells, and PSC express nicotinic acetylcholine receptors, which bind to nicotine and NNK, suggesting that cigarette smoke and its major components directly affect pancreatic cells.

Cigarette smoke and its components affect cell func-

tions and homeostasis in pancreatic cells [7, 52 and references therein] (Table 48.2). Cigarette smoke reduced pancreatic bicarbonate secretion in part by disrupting CFTR. NNK caused premature activation of trypsinogen and chymotrypsinogen in isolated pancreatic acinar

Table48.2 Effects of cigarette smoke and its components

onpancreatic cells[7,52].

1. induces mitochondrial damage

2. elevates intracellular calcium levels

3. disrupts expression and function of the CFTR in ductal cells

4. decreases fluid and bicarbonate secretion

5. induces endoplasmic reticulum stress

6. promotes oxidative stress

7. activates pancreatic stellate cells to promote fibrosis

CFTR: cystic fibrosis transmembrane conductance regulator.

cells. Nicotine activates multiple signal transduction pathways resulting in high levels of intracellular calcium release and cell injury. Clinically relevant concentrations of cigarette smoke component NKK could activate PSC, suggesting a potential mechanism for smoking- induced CP progression[53].

In animal studies, rats exposed to high- dose cigarette smoke for up to 12weeks developed a chronic inflammation resulting in pancreatic fibrosis and scarring of pancreatic acinar cell structure[54]. The ratio of trypsinogen to its endogenous trypsin inhibitor was elevated after chronic cigarette smoke exposure for 3months, suggesting an increased vulnerability to self- digestion of the pancreas[55]. Exposure to nicotine caused the production of reactive oxygen species in pancreatic acinar cells[56]. Both nicotine and NNK have been shown to induce morphological changes in the pancreas consistent with those seen in pancreatitis. Furthermore, nicotine affects pancreatic secretion and NNK induces premature zymogen activation, two well- known features of pancreatitis. These cigarette toxins may mediate both pro- and anti- inflammatory pathways and can induce changes in pancreatic acinar cell function at the level of transcription, leading to conditions such as thiamin deficiency and mitochondrial dysfunction. Such circumstances could leave the pancreas prone to the development of pancreatitis.

Cigarette smoke might contribute to CP development through the modulation of immune cells. Xue et al. reported a role of aryl hydrocarbon receptor agonists, such as dioxin and benzo[a]pyrene, in smokingassociated CP [57]. Aryl hydrocarbon receptor ligands in cigarette smoke induces IL- 22 production in CD4

T cells through aryl hydrocarbon receptors during the pancreatic damage. IL- 22interacts with IL- 22 receptor on PSC and upregulates production of extracellular matrix, leading to the development of pancreatic fibrosis. The role of IL- 22 was further supported by the higher serum IL- 22 levels in current smokers with CP. AhR ligands did not induce fibrosis in the absence of

References 401

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caerulein, suggesting that AhR activation by cigarette smoke alone is not sufficient, and additional pancreatic insults are required to induce CP.

Because most drinkers smoke, it is interesting to see the interaction between alcohol and smoking in CP. Lugea et al. [58] reported that smoking disrupts the protective adaptive mechanism that prevents ethanol- induced damage. Cigarette smoke extracts reduced spliced XBP1levels, and increased ethanol- induced oxidative and ER stresses, leading to cell death in pancreatic acinar cells. These might be mechanisms by which alcohol and smoking interact and worsen acinar cell injury and pancreatitis.

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404

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Idiopathic andRare Causes ofChronic Pancreatitis

Morihisa Hirota1 and Tooru Shimosegawa

Division of Gastroenterology, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan

South Miyagi Medical Center, Shibata County, Miyagi, Japan

Introduction

Chronic pancreatitis (CP) is now recognized as a heterogeneous inflammatory disease that can develop in individuals with multiple risk factors, including environmental and genetic factors [1,2]. Many risk factors have been described in the TIGAR- O and M- ANNHEIM classifications, which include alcoholic, smoking, genetic, autoimmune, obstructive, nutritional, and rare metabolic factors [3,4]. However, recent international consensus guidelines strongly agree that alcohol, smoking, and certain genetic alterations are risk factors forCP[5].

Idiopathic CP (ICP) is identified after ruling out other potential causes, including rare ones [2,6]. It has been proposed that ICP can be further classified into three types, primarily based on clinical features: early- onset ICP (EO- ICP), late- onset ICP (LO- ICP), and tropical pancreatitis (TP) [3]. This chapter mainly focuses on the clinical features of ICP, including EO- ICP and LO- ICP described in recent reports. Moreover, we discuss the background risk factors for ICP, which include environmental risk factors, such as smoking and consuming small amounts of alcohol, and genetic risk factors (7–11]. In addition, rare causes of CP are also described.

with ICP may include moderate or social drinkers [6]. Originally, ICP in patients with absolute abstinence from alcohol has been classified as EO- ICP or LO- ICP [12,13]. Thus, it is necessary to strictly distinguish between two categories of ICP, one that excludes all drinkers and one that includes people who drink small amounts of alcohol (light drinkers).

Classification

Early- Onset andLate- Onset

Patients with ICP who abstain from alcohol and were diagnosed at the Mayo Clinic had a bimodal age distribution. Their ICP has been classified into two types: EOICP or LO- ICP [6,12]. Age 35 is used as a cutoff for distinguishing between these two types of ICP [12]. Abimodal age distribution among patients with ICP has also been reported in Italy and among patients of European ancestry in the United States [13,14]. Although the peaks occurred at higher ages in a report from Japan, ICP showed a bimodal age distribution [15]. However, a bimodal distribution was not found in Chinese patients with ICP [16]. Since the latter two reports included light drinkers with ICP, light alcohol consumption might have affected the distribution of onset age [9,13]. Smoking and racial differences are other potential factors that should be studied in the future [6,17].

Idiopathic Chronic Pancreatitis

Definition

To date, heavy alcohol drinkers (usually 50–80 g or more per day) with CP have been defined as having alcoholic CP (ACP). In others, CP has been defined as ICP after excluding all known rare causes such as obstructive, hereditary, and autoimmune diseases. Therefore, patients

The Pancreas: An Integrated Textbook of Basic Science, Medicine, and Surgery, Fourth Edition. Edited by Hans G. Beger, Markus W. Büchler, RalphH. Hruban, Julia Mayerle, John P. Neoptolemos, Tooru Shimosegawa, Andrew L. Warshaw, David C. Whitcomb, and Yupei Zhao. © 2023 John Wiley & Sons Ltd. Published 2023 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/beger/thepancreas4e

Tropical Pancreatitis

TP is a type of ICP seen in tropical countries. It is characterized by large pancreatic calculi and ductal dilatation in a young malnourished patient who presents with abdominal pain, diabetes, or both [18]. It has been reported in many parts of tropical Asia and Africa, but mostly in India, especially in the states of Kerala and Tamil Nadu [19]. Although malnutrition and cassava

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intake were previously thought to be causally associated with TP, they are no longer implicated as causative factors [17].

In most studies, alcoholic was the most common etiology of CP, accounting for 33.6% to 72.0% of cases. The proportion of ICP cases was between 12.9% and 28.6% in the presented studies except for a nationwide study from

Prevalence

Table49.1 shows the etiologies of CP from recently published epidemiologic analyses in population- based, multicenter, or nationwide cross- sectional studies [20–28].

Table49.1 Etiology ofCP inepidemiologic studies.

Author [ref] Nation or region Study period Study design Number of patients Etiology

Lankisch etal. [20] Germany /

Lüneburg County

Wang etal. [21] China 1994–2004 Retrospective

Frulloni etal. [22] Italia 2000–2005 Prospective multicenter

Coté etal. [23] United States 2000–2006 Prospective multicenter

Ryu etal. [24] Korea 2001–2004 Retrospective

Balakrishnan etal. [25] India 2005–2007 Prospective multicenter

Hirota etal. [26] Japan 2007 Cross-

Conwell etal. [27] United States 2008–2012 Prospective multicenter

Masamune etal. [28] Japan 2016 Cross- sectional study 2102 ACP72.0%

1988–1995 Population- based study 74 ACP71.6%

multicenter study

study

multicenter study

study

India. The study showed the most common etiology was idiopathic, accounting for 60.2% of cases [25]. ICP was prominent in India. This finding was confirmed by three observational studies from single- centers in both northern and southern India [29–31].

ICP28.4%

2008 ACP35.1%

Biliary 34.4% Hereditary 7.2% ICP12.9%

893 ACP33.6%

Obstruction 26.7% Alcohol + obstruction 9.2% Autoimmunity 3.8% Dystrophy 6.2% Hereditary 4.0% ICP16.6%

539 ACP44.5%

Genetic 8.7% Autoimmune 2.2% Obstructive 8.7% Other 7.2% ICP28.6%

814 ACP64.3%

Obstructive 8.6% Autoimmune 2.0% Other 4.4% ICP20.8%

1033 ACP38.7%

Other 1.1% ICP60.2%

sectional study 1236 ACP69.7%

Obstructive 1.1% Hereditary 0.9% Other 7.3% ICP21.0%

521 ACP45.7%

Genetic 9.8% Obstructive 6.9% Autoimmune 1.5% Other 11.9% ICP24.2%

Hereditary 1.6% Obstructive 0.4% Autoimmune 0.4% Other 1.9% ICP23.7%

Ref: reference; ACP: alcoholic chronic pancreatitis; ICP: idiopathic chronic pancreatitis.

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406

Tropical Pancreatitis

It has been reported that the prevalence of TP has significantly decreased. Previously, it was reported that TP accounted for more than 50% of CP cases in India [18]. However, a nationwide study conducted from 2005 to 2007in India demonstrated TP made up only 3.8% of CP cases [25]. This finding was supported by a single- center observational study that demonstrated the proportion of typical TP was 5.8% [30]. Malnutrition, a typical feature of TP, has been rarely observed among patients with ICP in India. The prevalence of diabetes has decreased from 90% to 50% of ICP cases [17,30]. Furthermore, it has been pointed out that the number of drinkers is increasing due to lifestyle changes. The prevalence of ACP has been increasing in India [25]. The spectrum of clinical features in ICP has been changing in India and possibly other places.

Clinical Characteristics

Idiopathic vs. Alcoholic

ACP is generally recognized to cause severe symptoms [32]. To clarify the clinical characteristics of patients with ICP, seven reports comparing ICP and ACP from the United States, East Asia, and India were reviewed (Table49.2). In these studies, ICP included light drinkers. Since the three studies were single- center observational studies, selection bias was possible [29,30,33]. The background of patients might be different between multicenter studies at specialty hospitals [23,24] and nationwide cross- sectional surveys [15,28] that included general hospitals because young symptomatic patients are expected to concentrate in specialty hospitals. The two studies from Japan are nationwide surveys conducted in different years [15,28]. Therefore, many of the participants in these studies might be duplicated.

Table49.2 Comparison ofclinical features between ACP andICP.

Author [ref] Coté etal. [23] Hao etal. [33] Ryu etal. [24]

Hirota etal. [15]

Masamune etal. [28]

Bashin etal. [29]

Midha etal. [30]

Country United States China Korea Japan Japan India India

Study period 2000–2006 2000–2013 2001–2004 2011 2016 1999–2004 2004–2008

Number of patients

240 / 154 404 / 1633 523 / 169 1171 / 347 1513 / 498 59 / 64 157 / 242

(ACP/ICP)

Males, % (ACP/

70.0 / 41.6

98.3 / 63.1

96.0 / 66.7

92.2 / 54.6a91.0 / 60.0a100 / 65.6

99.4 / 63.6

ICP)

Age at onset, years

– 38.1 / 41.6

– 51.5 / 57.2a– – 37.9 / 24.7

(ACP/ICP)

Age at study, years

50.9 / 50.0 42.6 / 47.0

50.7 / 50.4 60.4 / 67.2a– 41.5 / 33.0a40.2 / 27.5

(ACP/ICP)

Ever smoker, %

92.9 / 58.6

80.7 / 22.8

– 85.0 / 39.8a79.8 / 41.5

70.7 / 12.8

(ACP/ICP)

Pain, % (ACP/ICP) – 94.6 / 91.8

Calcification, %

66.2 / 53.9

83.9 / 73.0

– 68.1 / 54.8a– 91.5 / 96.9 –

72.3 / 64.5 71.7 / 63.4a70.3 / 59.7a35.6 / 46.9 68.8 / 82.6

(ACP/ICP)

Diabetes, % (ACP/

29.2 / 26.4 38.9 / 26.3

35.0 / 26.0

40.1 / 30.5a43.1 / 40.3 22.0 / 23.4 36.3 / 35.5

ICP)

Exocrine

30.8 / 28.6 29.7 / 20.8

– – 33.6 / 30.5 28.0 / 12.0 6.3 / 16.9 insufficiency, % (ACP/ICP)

Pseudocyst, %

38.3 / 13.0

23.3 / 14.7

33.5 / 21.9

– 29.6 / 11.2a47.4 / 34.3 40.1 / 14.5

(ACP/ICP)

Biliary stricture, %

21.7 / 8.4

17.8 / 15.9 13.6 / 14.8 – 16.8 / 7.0

– 29.3 / 10.7

(ACP/ICP)

Surgery %, (ACP/

– 16.6 / 20.7 No differencec– 17.8 / 12.1a– –

ICP)

P < 0.05.

Type of pain was different (P < 0.001).

No specific numbers were given.

Ref: reference; ACP: alcoholic chronic pancreatitis; ICP: idiopathic chronic pancreatitis.

Idiopathic Chronic Pancreatitis 407

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Taking these potential biases into account, some characteristic features were demonstrated. First, compared to ACP, which has a male predominance, the proportion of male patients with ICP was relatively low. The majority of patients with ACP were smokers. Second, there were likely regional differences in the age of patients with ICP. In the United States and East Asia, age at onset was in the 40s and 50s, and age at the time of the study was approximately in the 40s to 60s. In India, age at onset was in the 20s and age at time of the study was approximately in the 20s and 30s. Patients with ICP in India were shown to be approximately 20 years younger than those in other countries. Conversely, patients with ICP in Japan were 10 years older than those in other East Asia countries and the United States. Third, in the United States and East Asia, patients with ACP tended to have a higher incidence of calcification and diabetes than patients with ICP. However, patients with ICP in India had more calcification than those with ACP. There were no significant differences between the proportion of patients with ICP and patients with ACP who have diabetes in India. Finally, a higher proportion of patients with ACP had pseudocyst formation. This finding was seen in almost all reports.

In summary, patients with ACP were predominantly male and smokers in all countries. They tended to have

more severe clinical features than patients with ICP. Compared with ACP, a higher proportion of patients with ICP are women. In the United States and East Asia, patients with ICP are as old as or slightly older than patients with ACP, except for patients in India, who developed ICP at a very young age. However, patients with ICP in India tended to have a high rate of pancreatic calcification and diabetes as complications, even though they were very young.

Early- Onset andLate- Onset

Comparisons of clinical features between EO- ICP and LO- ICP were reported in five papers, two from the United States and three from India (Table 49.3). Layer etal. reported the results of a single- center observational study from the Mayo Clinic [12]. Lewis etal. reported a multicenter study with 26 participating institutions in the United States [13]. These studies defined patients with ICP as strictly abstinent from alcohol, which excluded even social and light drinkers. The latter study only included patients of European ancestry. Conversely, three studies from India, which were all single-

center observational studies, did not define patients with ICP as strictly abstinent from alcohol [29–31].

According to Table49.3, which shows a comparison of

clinical features between EO- and LO- ICP, regional

Table49.3 Comparison ofclinical features between EO- ICP andLO- ICP.

Author [ref] Layer etal. [12] Lewis etal. [13] Bashin etal. [29] Midha etal. [30]

Country United States United States India (North) India (North 61%,

Study period 1976–1985 2000–2014 1999–2004 2004–2008 2004–2010

Number of patients (EO/LO) 25 / 41 61 / 69 41 / 23 171 / 71 111 / 94

Males, % (EO/LO) 44.0 / 56.1 37.7 / 18.8

Age at onset, years (EO/LO) 19.2 / 56.2

Age at study, years (EO/LO) – 30.1 / 64.3

Ever smoker, % (EO/LO) – 33.3 / 43.5 – 9.9 / 19.7 8.1 / 12.1

Pain, % (EO/LO) 100 / 75.6

Calcification, % (EO/LO) 56.0 / 36.6 45.9 / 50.7 46.3 / 47.8 – 95.5 / 97.9

Diabetes, % (EO/LO) 32.0 / 41.5 29.5 / 27.5 17.1 / 34.8 33.3 / 40.8 41.4 / 69.1

Exocrine insufficiency, % (EO/LO) 44.0 / 46.3 29.5 / 36.2 7.3 / 0 16.4 / 18.3 34.4 /53.2

Pseudocyst, % (EO/LO) 16.0 / 14.6 11.5 / 27.5

Biliary stricture,% (EO/LO) 0 / 7.3 – – 8.2 / 16.9

Surgery %, (EO/LO) 60.0 / 31.7

P < 0.05.

No statistical results were shown.

EO- ICP was defined based on age at diagnosis <30 years. LO- ICP was defined based on age at diagnosis >30 years.

EO- ICP was defined based on age at onset <30 years. LO- ICP was defined based on age at onset ≥30 years.

No specific numbers were given.

Ref: reference; EO: early- onset idiopathic chronic pancreatitis; LO: late- onset idiopathic chronic pancreatitis; ICP: idiopathic chronic pancreatitis.

20 / 58

96.1 / 69.2

23.0 / 29.0 – –

75 / 48 63.2 / 64.8 61.3 / 50.0

23 / 44

– – 28.2 / 42.5

95.1 / 100 88.3 / 84.5 No difference

– 11.7 / 21.1 7.4 / 10.6

Other 39%)

18.7 / 39.1

Rajesh etal. [31]

India (South)

15.0 / 38.1

–

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408

differences between the United States and India are remarkable. First of all, the patient composition was different. More patients in the United States had LO- ICP while more patients in India had EO- ICP. Compared with EO- ICP patients in the United States, EO- ICP patients in India were predominantly male. Age at EOICP onset was approximately 20 years in both the United States and India. Patients with EO- ICP in the two countries had generally similar clinical features with predominantly complaints of pain and similar complication rates to LO- ICP even though they were younger. Second, the clinical characteristics of patients with LO- ICP were different between the two countries. The age at LO- ICP onset was in the late 50s in the reports from the United States, while it was approximately 40 years in the reports from India. In the US studies, significantly fewer patients with LO-

ICP complained of pain compared to patients with EO- ICP. Conversely, most patients with LO- ICP in India complained of pain. Patients with LO- ICP in India had similar rates of pancreatic calcification and diabetes as patients in the United States, even though they were on average more than 10 years younger. Finally, in particular, patients with LO- ICP in southern India had high rates of pancreatic calcification, diabetes, and exocrine insufficiency [31]. In this report, although patients with EO- ICP were very young, almost all of them had pancreatic calcification [31]. One reason for these differences might be explained by differences in patient background such as a small amount of alcohol intake and smoking, but further research including genetic analysis would be required.

Background Risk Factors

Smoking

Cigarette smoking has been identified as an independent risk factor for the development of CP [7,8]. Smoking facilitates the development of pancreatic calcification and diabetes in patients with CP [15,34]. As shown in Table49.2, the association between ACP and smoking is strong. The combination of alcohol abuse and smoking produces a higher cumulative risk for CP [35]. An association between ICP and smoking has also been reported. Among patients in Italy, smoking increased the risk of pancreatic calcification and heavy smoking (>20cigarettes per day) was associated with diabetes [36]. A report from the Mayo Clinic showed that smoking increases the risk of pancreatic calcification in LO- ICP but not in EO- ICP. However, smoking did not affect development of exocrine or endocrine insufficiency [37]. In patients with EO- ICP in southern India, smoking was an independent significant risk factor for diabetes according to a multivariate analysis [31].

Small Amount ofAlcohol Intake

As mentioned above, in general ICP includes patients who drink small amounts of alcohol (<50 g per day). Lankisch etal. reported the effect of a small amount of alcohol intake on the clinical course of ICP. Patients with LO- ICP drinking less than 50 g of alcohol per day were younger at disease onset and reported more frequent and severe pain than patients with LO- ICP who did not drink any alcohol [9]. A systematic review and metaanalysis demonstrated a linear dose–response relationship between alcohol consumption and development of CP, which was monotonically increasing with no identifiable threshold [10]. This indicates that even intake of a small amount of alcohol is a risk factor for CP.

Genetic Factors

Associations have been identified between several gene variants and ICP risk. In idiopathic disease, full sequence analysis of the following genes has been recommended in international consensus guidelines: cationic trypsinogen (PRSS1), carboxypeptidese A1 (CPA1), serine protease inhibitor Kazal type 1 (SPINK1), chymotrypsinogen C (CTRC), carboxyl ester lipase (CEL), and cystic fibrosis transmembrane conductance regulator (CFTR) [5]. Variants of these genes are classified into three categories according to mechanisms in the pathogenesis of CP. Variants of PRSS1, SPINK1, and CTRC are involved in the trypsin- dependent pathway. Variants of CPA1 and CEL are involved in the misfolding- dependent pathway, which is associated with protein misfolding and endoplasmic reticulum stress. Variants of CFTR are involved in the ductal pathway, which is related to disruption of chloridebicarbonate channel activity in pancreatic duct cells [2,11]. Mutations in PRSS1 and CPA1 are associated with >300fold and 25- fold higher risk of CP, respectively; thus, they are occasionally referred to as hereditary CP. The other gene variants have relatively low risk effects and are associated with sporadic CP with no family history [5].

A US multicenter study reported that 49% of patients with EO- ICP carried a pathologic variant associated with one or more of the following genes: CFTR, SPINK1, and CTRC. A SPINK1 mutation significantly accelerated the onset of symptoms in the EO- ICP group, from age 22 to age 12 [13]. A study from India reported that the SPINK1 N34S mutation was present in 42% of patients with ICP, which was significantly higher than the percentage in patients with ACP (17%) and controls (4%). This study also reported that 50% of patients with ICP and 10% of controls had CFTR variants [30]. Heterozygous SPINK1 mutations reportedly do not cause pancreatitis. It appears that patients with heterozygous SPINK1 mutations must also have a mutation in other susceptibility genes (e.g., PRSS1 or CFTR) in order to develop recurrent acute pancreatitis (RAP) or CP [38].

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